Poor bioavailability of water insoluble compounds has long been a problem in the pharmaceutical and diagnostics industry. While compounds with an aqueous solubility of greater than 1% w/v are not expected to present dissolution-related bioavailability and absorption problems, many new chemical entities exhibit aqueous solubility much below this value (see Pharmaceutical Dosage Forms—Tablets, Vol 1, page 13, Edited by H. Lieberman, Marcel Dekker, Inc, 1980). Many highly useful compounds are dropped from development or are formulated in a manner otherwise undesirable due to poor water solubility. A great number of these compounds are unstable in aqueous media and some require dissolution in oil, rendering the dosage form often unpleasant to take or even painful to use via the parenteral route of administration. This can lead to poor patient compliance and potentially an overall greater expense in treatment due to unnecessary hospitalizations. It is therefore desirable to develop a formulation of these water insoluble compounds that can be dosed in the simplest possible form: a rapidly dispersing solid dosage form.
Many methods exist for preparing rapidly dispersing solid dosage medicaments. Traditional approaches to this problem have involved the dispersion of a biological active ingredient with pharmaceutically acceptable excipients using mix techniques and/or granulation techniques. Specific functional excipients known in the art can be employed to aid in liberating the medicament, as for example effervescent disintegration agents(s) as taught by U.S. Pat. No. 5,178,878.
As a method of improving the disintegration of the solid dosage form, thereby liberating the medicament, freeze drying techniques have been previously employed as taught by U.S. Pat. Nos. 4,371,516; 4,758,598; 5,272,137. Additionally, spray drying techniques have been employed for similar purposes as for example, U.S. Pat. No. 5,776,491 which teaches the use of a polymeric component, a solubilizing component and a bulking agent as a matrix forming composition upon spray drying. This particulate matrix rapidly disintegrates upon introduction of an aqueous environment to release the medicament. Although these approaches produce rapidly liberating solid dosage forms, they suffer from a number of disadvantages particularly with medicaments that are water insoluble or poorly water-soluble. In these cases, suspensions of water insoluble compounds are likely to sediment prior to completion of the freeze-drying or spray drying process leading to particle aggregation and potentially inhomogeneous dry dosage forms. Additionally, large macromolecules of polysaccharides, typified by dextrans, when utilized as matrix formers have been implicated in agglomeration tendencies in reconstituted freeze-dried suspensions of liposomes (Miyajima, 1997). Therefore, the proper selection and employment of saccharide matrix formers remains elusive, we believe it is linked to the surface physicochemical nature of the water insoluble particle under consideration.
Additionally, suspensions of water insoluble compounds will be subjected to unwanted particle size growth as a result of the process of Ostwald ripening. In order to curtail this process, stabilization of these micronized materials suspended in an aqueous environment can be achieved by using compositions of a variety of pharmaceutically acceptable excipients known to those skilled in the art. Such approaches can be found, as example, in the commonly assigned U.S. Pat. Nos. 5,631,023 and 5,302,401 and EP0193208.
For instance, U.S. Pat. No. 5,631,023 discloses a method to prepare rapidly dissolving tablets (10 seconds) using Xantham gum at a maximum weight percent of 0.05 as the suspending and flocculating agent with gelatin in which is dispersed water insoluble drug particles. Mannitol is used as the preferred cryoprotectant. The suspension is freeze-dried in molds to generate the solid dosage form.
U.S. Pat. No. 5,302,401 describes a method to reduce particle size growth during lyophilization. It discloses a composition containing particles having a surface modifier adsorbed onto the surface together with a cryoprotectant, the cryoprotectant present in an amount sufficient to form a nanoparticle-cryoprotectant composition. A preferred surface modifier is polyvinylpyrrolidone, and a preferred cryoprotectant is a carbohydrate such as sucrose. Also described are methods of making particles having a surface modifier adsorbed on to the surface and a cryoprotectant associated with it. The patent refers specifically to 5% Danazol with 1.5% PVP and sucrose (2%) or mannitol (2%) as the cryoprotectant. Thus while various cryoprotectants are available and function adequately to protect the active agent during lyophilization, the solid product that results is often difficult to redisperse in aqueous media.
EP 0193208 describes a method of lyophilizing reagent-coated latex particles to allow for reconstitution without aggregation and discusses the need to incorporate a zwitterionic buffer such as an amino acid, a stabilizer such as PVP or bovine albumin and a cryoprotectant such as Dextran T10 or other polysaccharide.